Erythropoietin (EPO) is a glycoprotein hormone mainly produced in adult kidney and fetal liver. EPO exerts its effect by binding to erythropoietin receptor (EPO receptor) on cell surface. When cells sense a relatively low oxygen level (such as the hypoxia), EPO will be produced and released to regulate the proliferation, differentiation, maturation, and survival in erythroid lineage cells. Abnormal EPO levels in the blood stream could be the indicator for bone marrow and renal diseases. Relatively lower EPO levels are seen in patients with CKD, primary polycythemia rubra vera and chemotherapy-induced anemia.
Besides to be produced in kidney and liver, the expressions of EPO and EPO receptor are also found in non-erythroid tissues and organs, including brain, eye, heart, lung, gut, pancreas, muscle, uterus and gonads. Endogenous EPO-EPO receptor signaling contributes to wound healing responses, angiogenesis and local tissue-protective functions, such as neuroprotection, cardiovascular protection and protection from tissue ischemia and ischemia/reperfusion injury. It is reported that EPO treatment has renoprotective effects by reducing the extent of renal dysfunction and facilitating the recovery from cisplatin-induced acute renal failure.
Erythropoiesis-stimulating agents (ESAs) are recommended by the National Kidney Foundation Kidney Disease Outcomes Quality Initiative guidelines to treat anemia of CKD in patients with treatment-responsive anemia. Recombinant human EPO (rHuEpo) is approved for use in anemia of CKD, anemia in cancer patients receiving chemotherapy, to reduce transfusion requirements in surgical patients and to treat anemia in zidovudine-treated patients infected with the human immunodeficiency virus. A novel erythropoiesis stimulating protein (NESP), designed from EPO with longer plasma half-life, has been approved for the treatment of anemia by chronic renal failure. It is recommended that intravenous (i.v.) or subcutaneous (s.c.) administration should be more than once per week for maintenance therapy. However, the pain, the inconvenience for frequent injection and the development of anti-Epo antibodies due to the inherent antigenicity of rHuEpo should all be concerned. Furthermore, ESAs have safety risks in patients with higher hemoglobin levels and have complications such as hypertension, thromboembolism, iron deficiency and severe pure red-cell aplasia. Accordingly, an improvement in stimulating erythropoiesis and/or enhancing kidney functions is desired.
EPO is essential for the regulation of the mass of erythrocytes in response to changes in tissue oxygenation during hypoxia and anemia. The protective effects of EPO have been demonstrated in various tissues and experimental models of ischemia-induced injury and have been attributed to its effect on non-haematopoietic metabolic adaptation, inhibition of apoptosis and stimulation of angiogenesis. Recently, EPO has been reported to stimulate cardiac mitochondrial proliferation through the activation of mitochondrial biogenesis, which is mediated by PPAR co-activator 1-α (PGC-1α), a key regulator of cardiac bioenergetics. Clinically, EPO reverses cardiac remodeling, improves cardiac function, and enhances the exercise tolerance and quality of life of patients by inducing protective effects beyond the correction of anemia. These findings highlight the possibility that EPO-mediated protection may depend on its modulatory effects on intracellular energetics.
Hemoglobin (Hb) is the main oxygen transporter in erythrocytes. Its main form, Hb-α, is a tetramer consisting of two α- and β-polypeptide chains, each carrying a haeme group. Recently, Hb was unexpectedly found to be expressed in many non-haematopoietic cells and it is possible that it facilitates tissue oxygen transport or increases cellular oxygenation and so provides an intrinsic protective mechanism against hypoxic/ischemic injury.
EPO acts primarily to regulate erythropoiesis in the bone marrow by stimulating erythroid progenitor cell survival, proliferation and differentiation to produce mature red blood cells. EPO receptor expression on endothelial cells, the endometrium (lining) of the uterus, skeletal muscle myoblasts, the heart, and endothelial cells and neural cells in the retina and brain allows EPO to also act as a survival or mitogenic factor on these nonhaematopoietic cells, providing the potential for a response to EPO in multiple tissues. EPO has been used widely for the treatment of anemia associated with chronic kidney disease and cancer chemotherapy for nearly 30 years.